A Textbook Case of Human T-lymphotropic Virus-1 (HTLV-1)-Induced Adult T-cell Leukemia Treated With Cyclophosphamide, Hydroxydaunorubicin, Oncovin, and Prednisone/Prednisolone (CHOP)

Human T-lymphotropic virus-1 (HTLV-I) is an enveloped, single-stranded RNA virus of the Retroviridae family. The virus causes two well-recognized disease associations: adult T-cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP). We report a case of HTLV-1-induced adult T-cell lymphoma/leukemia in a 45-year-old female who presented with complaints of swelling on the right side of her neck and rash on her upper and lower extremities and abdomen. The patient also had a history of strongyloidiasis infection and Crohn's disease. She was found to have hypercalcemia and multiple lytic lesions of the bone found on the imaging. She also tested positive for HTLV-1 and T cell-positive for cluster of differentiation (CD) 2, CD3, partial CD5, and minimal CD56, later confirmed by the bone marrow (BM) and skin punch biopsies. ATL is characterized by the clonal proliferation of CD4+ T cells containing randomly integrated HTLV-I provirus, often associated with T-cell receptor gene rearrangements. ATL, in its aggressive forms, has one of the poorest prognoses of non-Hodgkin lymphoma. It is essential to raise awareness of ATL, although further research and trials are needed to solidify the treatment options to prevent mortality.


Introduction
Adult T-cell Lymphoma has four types depending on the presentation-acute, lymphomatous, chronic, and smoldering [1].Acute's Clinical features include skin lesions (nodules, ulcers, generalized widespread rash), lytic bone lesions, hypercalcemia, and pulmonary infiltrates with elevated serum CD25 (interleukin-2 receptor), serum thymidine kinase activity, and serum neuron-specific enolase Lymphomatous clinical features include lymphadenopathy, hepatosplenomegaly, and skin lesions [2].Hypercalcemia does not occur in the chronic type, and no CNS or gastrointestinal involvement exists.Smoldering presented with skin and pulmonary lesions does happen, but other clinical features such as lymphadenopathy, hepatosplenomegaly, and hypercalcemia are absent [3].

Case Presentation
A 45-year-old female from Ghana (recent visit in 2021, immigrated in 2017) with a past medical history of hypertension, pre-diabetes, lumbar spine radiculopathy with disc herniation, Crohn's disease, tension headaches, strongyloidiasis, H. pylori infection, and asymptomatic thymic enlargement presented with a papular, painful and itchy rash for one month.The rash started on the back of her hands and then extended distally, involving the feet, extensor surfaces, abdomen, and buttocks.The patient visited her primary care physician two weeks ago, and oral allergy medications plus topical medications were prescribed along with the discontinuation of gabapentin, but that did not help the rash.The patient endorsed nausea and vomiting for the past week, weight loss of an unknown amount, and right-sided neck swelling with tenderness.She denied smoking, drinking, or illicit drug use.The patient was febrile and hemodynamically stable, and the labs on the initial presentation are mentioned in  On physical exam, the neck was noted to have tenderness and mobile anterior cervical right-sided lymph nodes.The rash was raised with hyperpigmentation and scaling.A CT of the abdomen and pelvis revealed bilateral iliac and groin lymphadenopathy and widespread lytic bone lesions, suggesting widespread bony metastatic disease, as shown in Figure 1.A CT chest without contrast revealed supraclavicular lymphadenopathy right worse than left and multiple pulmonary nodules, the most severe being 3mm in the upper right lobe.Lab work revealed lactic acidosis 2.3 mmol/L (normal <2 mmol/L) and hypercalcemia with Ca 14 mg/dL (normal 8.6-10.3mg/dL).Based on lab and CT findings, the patient was admitted to the Intensive Care Unit.The patient started on the topical ointment diflorasone.Laboratory tests were sent for HTLV, lymphoma, and multiple myeloma electrophoresis.

Discussion
Human T lymphotropic virus type 1 (HTLV-1) is a CD4+T retrovirus.It was first discovered by the Gallo Group in 1979 [4].A set of patients established by J. Minna and A. Gazdar became the first documented detection of HTLV-1 within their T cell line [4].These patients exhibited the virus' rare yet lethal sequelaecutaneous T cell Lymphoma [4].There are currently seven known subtypes of HTLV-1, A-F, containing several strains originating in various African and Asian countries [5,6,7].While this virus is considered a rising epidemic and infects the host indefinitely, the virus typically yields little immunosuppression to those infected.Approximately 95% of individuals who contract the virus remain lifelong asymptomatic carriers.The remaining 5% of those with HTLV-1 may succumb to malignancies, inflammatory or opportunistic pathology [8,9].
The major routes of viral transmission include vertical transmission, sexual transmission, and transmission via blood transfusion [10].While sexual contact is the most common mode of transmission, vertical transmission in childhood is a significant factor in developing associated Adult T-cell Lymphoma [11,12].Vertical transmission from breast milk increases the risk for transmission of HTLV1 to a child by four times, a substantial margin [13].Several clinical manifestations coincide with HTLV1 infection.One example is infective dermatitis (ID).ID is considered vertical transmission dependent, as the onset begins before two years of age and resolves before adulthood.ID is not a manifestation of HTLV1 isolated to childhood, as emerging cases of adult-onset ID associated with HTLV1 infection have been recently described [14,15,16,17] Strongyloidiasis infection is strongly associated in those with symptomatic associations with the HTLV-1 virus.Stronglyoides' infective course is either asymptomatic or mild in the healthy population [18].The danger lies in the development of autoinfection, where larvae enter the bloodstream and disseminate throughout the body [18].The HTLV-1-infected individual lies vulnerable to autoinfection due to a decrease in native anti-helminthic protective measures of the immune system, leading to a substantial increase in the frequency of disseminated Stronglyiodes infection amongst HTLV-1 infected individuals [19].
Adult T cell Lymphoma caused by HTLV-1 and its subtypes are rare neoplasms with CD4+ CD25+ T cell markers [20].This lymphoma/leukemia is aggressive and can carry a grimmer prognosis than its non-Hodgkin lymphoma counterparts [21].Due to the heterogeneity in profiles of associated Adult T cell Lymphoma, the malignancy is further divided into four types of sub-categories: acute, lymphoma, chronic, and smoldering.Acute is regarded as the more aggressive of the four subtypes [22].Furthermore, paraneoplastic hypercalcemia is one of the most common and most lethal consequences of Adult T-cell Lymphoma.The proposed mechanism of hypercalcemia is due to inappropriate bone resorption via excessive osteoclast accumulation [23].Adult T cell Lymphoma-associated hypercalcemia is a consequence of several cytokine activations such as interleukin-1 and transforming growth factor β [24,25].Moreover, inappropriate expression of PTH-rP, while not consistently increased in Adult T-cell Lymphoma hypercalcemia, plays a fundamental role in Adult T-cell Lymphoma hypercalcemia, particularly in immunodeficient mice models implanted with leukemic cells [26].Serum calcium levels are increased in approximately 70% of HTLV-1-positive individuals with Adult T cell Lymphoma and is one of the most significant increases in mortality within this patient population [26].

Conclusions
In our case of the presented patient, she not only presented with one pathological correlate but several, including dermatologic manifestations, hypercalcemia, and previous Strongyloidiasis infection.ATL, in its aggressive forms, carries one of the poorest prognoses in non-Hodgkin lymphoma.This case report illustrates the diverse complexity of patients with ATL.It is one of the few cancers which are caused by a virus.The findings are only sometimes typical.Recent advances in oncology and hematology have shown promising results for mogamulizumab and lenalidomide.As physicians, we should keep a low threshold for these diagnoses.It is essential to raise awareness of ATL, although further research and trials are needed to solidify the treatment options to prevent mortality.

FIGURE 1 :
FIGURE 1: CT Abdomen and Pelvis showing bilateral iliac lymphadenopathy and erosive lesions of the spine, and iliac bones.Red arrows shows erosive lesions

FIGURE 2 :FIGURE 3 :
FIGURE 2: Trend of Serum Calcium x-axis shows days of the hospital course y-axis shows serum calcium in mg/dL